Whenever a medical device comes in contact with a patient, a risk of infection is created. Thus, a contaminated examination glove, tongue depressor, or stethoscope could transmit infection. The risk of infection dramatically increases for invasive medical devices, such as intravenous catheters, arterial grafts, intrathecal or intracerebral shunts and prosthetic devices, which not only are, themselves, in intimate contact with body tissues and fluids, but also create a portal of entry for pathogens.
Catheter related infections, especially blood stream infections, are associated with increased morbidity (10 to 20 percent), prolonged hospitalization (by a period having a mean of seven days), and increased medical costs (approximately $6,000 per hospitalization). According to a survey of intensive care units from 1986 through 1990 by the National Nosocomial Infection Surveillance System, the rate of catheter-related blood stream infections ranged from 2.1 to 30.2 per 1,000 catheter-days. Infections associated with central venous catheters have been reported to result from the transcutaneous migration of the pathogens from the insertion site with the eventual colonization of the catheter tip. In addition, intraluminal colonization has been suggested to result from contaminated hubs and infusates that contribute to catheter related blood stream infections. The longer the duration of catheterization, the greater the susceptibility to either luminal or outer surface colonization of catheters. Even for short term use of catheters, infections have been reported due to contamination of the insertion sites.
A number of methods for reducing the risk of infection have been developed which incorporate anti-infective agents into medical devices. Such devices desirably provide effective levels of anti-infective agent during the period that the device is being used. Sustained release may be problematic to achieve, in that a mechanism for dispensing anti-infective agent over a prolonged period of time may be required, and the incorporation of sufficient amounts of anti-infective agent may adversely affect the surface characteristics of the device. The difficulties encountered in providing effective antimicrobial protection increase with the development of drug-resistant pathogens.
One potential solution to these problems is the use of a synergistic combination of anti-infective agents that requires relatively low concentrations of individual anti-infective agents which may have differing patterns of bioavailability. For example, WO 97/25085 relates to medical devices comprising synergistic combinations of chlorhexidine and triclosan. U.S. Pat. Nos. 5,616,338 and 5,019,096 relate to infection resistant medical devices comprising synergistic combinations of a silver salt, a biguanide (such as chlorhexidine) and a polymeric component that forms a matrix to provide a sustained release of the silver salt and biguanide.
U.S. Pat. Nos. 5,165,952 and 5,451,424 relate to medical articles with chlorhexidine both coated on and bulk distributed throughout the medical articles. When chlorhexidine is bulk distributed it adversely affects certain characteristics of the device such as tensile strength, and the high temperatures needed for extension of plastics such as polyurethane may damage the chlorhexidine.
U.S. Pat. No. 5,089,205 relates to incorporation of chlorhexidine free base or one of its salts in a medical device such as a glove by both a distribution or dipping process.
Chlorhexidine is a broad spectrum antimicrobial agent and has been used as an antiseptic for several decades with minimal risk of developing resistant microbes. When relatively soluble chlorhexidine salts, such as chlorhexidine acetate, were used to impregnate catheters, the release was undesirably rapid. The duration of the antimicrobial efficacy of medical devices impregnated with chlorhexidine salts, such as chlorhexidine acetate, is short lived. Chlorhexidine free base is not soluble in water or alcohol and cannot be impregnated in sufficient amounts because of low solubility in a solvent system.
In contrast to the present invention, none of the above-cited references teach medical articles treated with a solution comprising a combination of chlorhexidine free base and a water-soluble chlorhexidine salt, at particular ratios, which provide improved antimicrobial effectiveness through an increased uptake of chlorhexidine into the medical device, increased retention of chlorhexidine in the medical device and prolonged release of chlorhexidine from the medical device, while utilizing relatively low levels of chlorhexidine,